1. Field of the Invention
The present invention relates to antibodies which are specific to quinolinic acid.
2. Description of the Background
Quinolinic acid (QUIN), a metabolite of the kynurenine pathway of tryptophan degradation, is an endogenous neurotoxin which produces excitatory responses in neurons of the mammalian central nervous system. QUIN is produced at an increased rate generally during any physical stress which causes swelling, such as infection, and an increased level of QUIN in the blood or cerebrospinal fluid is indicative of the extent of a particular infection.
Generally, any physical stress causing swelling, including any pathological assault on the body, blunt force injury or even anoxia triggers an increase in QUIN level in blood or cerebrospinal fluid. Studies have indicated that mononuclear phagocytes, and particularly macrophages, produce significant quantities of QUIN.
The excitatory effect produced by QUIN is known to be mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Excessive activation of neuronal NMDA receptors by QUIN and related compounds leads to prolonged calcium influx and eventual neuronal death. When compared with other endogenous excitatory compounds such as glutamate and aspartate, which are only mildly neurotoxic at high concentrations, QUIN is perhaps 100 times more toxic to neurons bearing NMDA receptors.
It is also known that glial cells throughout the central nervous system contain enzymes in the kynurenine pathway of tryptophan metabolism responsible for the synthesis and degradation of QUIN. These cells have been implicated in the production of QUIN in the brain under both normal and pathological conditions.
The concentration of QUIN in the blood, cerebrospinal fluid and brain may become significantly elevated as a result of numerous peripheral and central pathologies. However, it is also known that peritoneal administration of endotoxins increases the level of QUIN in the body, including the brain, to a significant extent.
Although glial cells have been thought to be a source of brain QUIN, it is now considered that there are additional sources. For example, when the central nervous system is under infection by polio virus, increases in the activity of the rate limiting enzyme in the kynurenine pathway, indolamine 2,3-deoxygenase (IDO), can be correlated with increases in QUIN concentration and the severity of central nervous system inflammation.
Further, it has also been reported that compounds released by HIV-I infected microglia are neurotoxic in vitro. This effect is also mediated by the NMDA type of neuronal glutamate receptor.
Additionally, inasmuch as QUIN is a selective NMDA receptor agonist whose systemic and central concentrations are responsive to infection, immune stimulation or damage, QUIN appears to be a significant macrophage/microglia secreted neurotoxin. Although QUIN was not initially detected in neurotoxic supernatants from HIV-I infected mononuclear phagocyte cultures, it was subsequently determined that human macrophages convert tryptophan to QUIN, and at an increased rate under stimulation by .gamma.-interferon or HIV-1 infection in vitro, leading to neurotoxic levels of QUIN in the culture medium. Thus, QUIN appears to be implicated as causative agent of inflammation-mediated excitotoxic neurodegeneration.
Presently, mass spectrometry (MS) is used to detect the concentration of QUIN in a liquid sample. Unfortunately, however, mass spectrometries and gas chromatographs, often used in tandem therewith, are very expensive, and techniques using this equipment are time consuming and require specially trained operators. It would be extremely advantageous if a means were known for performing quantitative analyses of QUIN in fluid samples in a simplified and inexpensive manner.
It would also be quite advantageous if a means were known by which the cellular origins of QUIN could be accurately and rapidly ascertained.